Molecular mechanisms of the maternal to zygotic transition

母体向合子转变的分子机制

• 批准号: 9277085
• 负责人: Antonio J Giraldez
• 金额: $ 70.5万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9277085
• 关键词: Advanced Development; Affect; Age; Animals; Biological Assay; Cells; Chromatin; Code; Development; Embryo; Embryonic Development; Fertilization; Fertilization in Vitro; Gene Expression; Genes; Genetic Transcription; Genome; Goals; High-Throughput Nucleotide Sequencing; Hour; Human; Individual; Infertility; Instruction; Malignant Neoplasms; Maps; Maternal Messenger RNA; Messenger RNA; Methods; MicroRNAs; Modification; Molecular; Oncogene Activation; Output; Pathway interactions; Play; Post-Transcriptional Regulation; Pregnancy; Pregnancy loss; Process; Proteins; Public Health; RNA; RNA-Protein Interaction; Reader; Recruitment Activity; Regulation; Regulator Genes; Repression; Reproductive Health; Role; Shapes; Structure; System; Translations; Woman; egg; experimental study; human disease; in vivo; insight; mRNA Decay; mRNA Stability; novel; programs; reproductive; tool; transcriptome; vertebrate embryos; zygote

SUMMARY The maternal to zygotic transition is a universal step in animal development, where the embryo transitions from a maternally driven program to a zygotic program. This requires the clearance of the maternally provided mRNAs, and transcription of the zygotic genes. Indeed, these two processes are intimately interconnected, maternal factors drive the activation of the zygotic genes, and zygotic products actively target maternal mRNAs for deadenylation, repression and clearance. While recent studies have identified individual factors regulating mRNA stability and activation of the zygotic genome, we lack major understanding on 1) how different regulatory mechanisms are integrated to instruct mRNA turn over and translation regulation in the embryo, 2) what are the mechanisms that regulate protein output and genome activation, and 3) what is the regulatory code (sequences, structures and RNA modifications) that shape genome activation and post-trasncriptional regulation. By combining high throughput sequencing, protein-RNA interaction maps, with novel methods to assay the regulatory activity of the transcriptome in the early embryo, we will define the factors that are recruited to the genome to activate the zygotic program, the mechanisms that activate the chromatin, the sequence/structural motifs (code) that determine maternal mRNA fate, the readers that interpret the code and the mechanisms that trigger each of these steps in vivo. Together these proposed experiments, will define the gene regulatory network that controls early vertebrate development. The proposed project is relevant for public health at different levels. First, from the stand point of human disease and cancer, pathways that control mRNA stability (including miRNAs) play an important role in aberrant oncogene activation in cancer, and are relevant to changes in cell fate where the cells need to install a new program and remove the previous cellular program through post-transcriptional regulation. Second, from the stand point of reproductive health, infertility is estimated to affect 15% of reproductive age women and early pregnancy loss corresponds to 25% of all pregnancies with up to 70% in pregnancies after in vitro fertilization. Understanding of the mechanisms of zygotic genome activation and maternal mRNA decay can provide fundamental insights in human infertility and tools to evaluate early loss of fertilized eggs. The results derived from this project will help us understand how gene expression is regulated in the early embryo during the maternal to zygotic transition to ultimately trigger the activation of the different developmental pathways during embryogenesis.

概括 母体到合子的转变是动物发育中的普遍步骤，其中胚胎 从母体驱动程序转变为合子程序。这需要获得相关部门的许可 母体提供 mRNA，以及合子基因的转录。确实，这两个过程是 密切相关的母体因素驱动合子基因的激活，并且合子 产品主动针对母体 mRNA 进行去腺苷化、抑制和清除。 虽然最近的研究已经确定了调节 mRNA 稳定性和激活的个体因素 对于合子基因组，我们缺乏对以下方面的主要了解：1）不同的调控机制有何不同 整合以指导胚胎中的 mRNA 转换和翻译调控，2) 什么是 调节蛋白质输出和基因组激活的机制，以及 3) 调节代码是什么 （序列、结构和 RNA 修饰）塑造基因组激活和转录后 规定。通过将高通量测序、蛋白质-RNA 相互作用图谱与新颖的 检测早期胚胎转录组调节活性的方法，我们将定义 被招募到基因组中以激活合子程序的因子，即激活的机制 染色质、决定母体 mRNA 命运的序列/结构基序（代码）、读者 解释体内触发每个步骤的代码和机制。一起这些 拟议的实验将定义控制早期脊椎动物的基因调控网络 发展。 拟议项目与不同层面的公共卫生相关。首先，从人的角度来看 疾病和癌症中，控制 mRNA 稳定性（包括 miRNA）的途径在 癌症中癌基因的异常激活，与细胞命运的变化有关，细胞需要 通过转录后调节安装新程序并删除以前的细胞程序。 其次，从生殖健康的角度来看，不孕不育估计影响15%的生殖健康。 高龄妇女和早期妊娠流产占所有妊娠的 25%，其中高达 70% 体外受精后怀孕。了解合子基因组激活机制 母体 mRNA 衰变可以为人类不孕症提供基本见解和评估工具 受精卵过早流失。 该项目的结果将帮助我们了解基因表达是如何在 母体向合子过渡期间的早期胚胎最终触发不同的激活 胚胎发生过程中的发育途径。